CRF receptor 1 (CRF 1), a key neuroendocrine mediator of the stress response, has two known agonists corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1). Here we report that endothelin- converting enzyme-1 (ECE-1) differentially degrades CRF and Ucn1; ECE-1 cleaves Ucn1, but not CRF, at critical residue Arginine-34/35 , which is essential for ligand-receptor binding. At near K D agonist concentration (30 nM), both Ucn1- and CRF-mediated Ca 2+ mobilization are ECE-1 dependent. Interestingly, at high agonist concentration (100 nM), Ucn1-mediated Ca 2+ mobilization remains ECE-1 dependent, whereas CRF-mediated mobilization becomes independent of ECE-1 activity. At high agonist concentration, ECE-1 inhibition disrupted Ucn1-, but not CRFinduced CRF1 recycling and resensitization, but did not prolong the association of CRF 1 with I?-arrestins. RNA interference-mediated knockdown of Rab suggests that both Ucn1- and CRFinduced CRF 1 resensitization is dependent on activity of Rab11, but not of Rab4. CRF 1 behaves like a class A G protein-coupled receptor with respect to transient I?-arrestins interaction. We propose that differential degradation by ECE-1 is a novel mechanism by which CRF 1 receptor is protected from overactivation by physiologically relevant high concentrations of higher affinity ligand to mediate distinct resensitization and downstream signaling.